With the number and quality of human genome sequences increasing rapidly, connecting the variation between individuals to particular functional changes and phenotypes is the next major challenge. The goal of my research is to bridge the gap between the sequencing data and functional understanding, focusing on the vitamin D signaling cascade. Vitamin D signaling is critical to human health, and altered signaling has been implicated in numerous disease states, including cancer, autoimmune dysfunction, rickets, and several infectious diseases. Human genome sequencing projects, like the 1000 Genomes Project, have identified signal nucleotide polymorphisms (SNPs) within the vitamin D receptor (VDR) gene, yet whether and how these SNPs affect the function of VDR is relatively unknown. To tackle this problem, we will create a vitamin D signaling assay in yeast to determine if variants of VDR that exist in the population affect its ability to act as a transcripton factor. This assay will allow us to screen variants in a high-throughput manner, while avoiding the endogenous negative feedback regulation of vitamin D. We will also determine if variants that abrogate vitamin D signaling are vitamin remedial by higher concentrations of vitamin D. After we have identified variants that impact VDR function, we will determine if they are able to alter a disease phenotype. Macrophages utilize vitamin D signaling to induce autophagy when they sense an infection, such as by Mycobacterium tuberculosis. I will create macrophage cell lines that exclusively express variant VDRs, and assess if these macrophages are capable of mounting autophagic responses to a simulated M. tuberculosis infection. By identifying VDR variants that abrogate the macrophage response to infection, we could identify individuals that have a genetically determined higher requirement for vitamin D.